While a large number of compounds are known which possess central nervous system depressant activity, most possess certain disadvantages, such as exhibiting a high order of toxicity, insufficient activity or a tendency to be habituating. Thus researchers are constantly re-examining known compounds or synthesizing new ones in order to find more satisfactory agents possessing central nervous system depressant activity.
This invention relates to new compounds possessing central nervous system depressant properties of the formula ##SPC1##
Wherein R may be hydrogen or a straight or branched chain alkyl radical of from 1 to 4 carbon atoms, aryl of from 6 to 10 carbon atoms, or aralkyl of from 7 to 10 carbon atoms; R.sup.1 is hydrogen or a straight or branched alkyl radical having from 1 to 4 carbon atoms; R.sup.2 and R.sup.3 may be hydrogen, alkyl of from 1 to 4 carbon atoms, CF.sub.3, F, Cl or Br; R.sup.4 may be
1. a substituted straight or branched chain alkyl radical of up to 10 carbon atoms which alkyl radical is substituted by phenyl or a substituted phenyl radical wherein the phenyl substituent is halogen, CO.sub.2 alkyl, CN, NC, CF.sub.3, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or dialkylsulfonamide wherein the dialkyl radicals have a total of 6 carbons; PA1 2. a mono- or di-unsaturated straight or branched chain hydrocarbon radical of from 3 to 10 carbon atoms wherein the carbon atom attached to the oxygen atom is saturated; PA1 3. a substituted mono- or di-unsaturated straight or branched hydrocarbon radical of from 3 to 10 carbon atoms wherein the carbon atoms attached to the oxygen atoms is saturated and which hydrocarbon radical is substituted by phenyl or a substituted phenyl radical wherein the phenyl substituent is as set forth previously, or by a halogen atom on a carbon atom carrying a double bond, and the pharmaceutically acceptable acid addition salts thereof, such as the hydrochloride, hydrobromide, sulfate, phosphate, maleate, fumarate, citrate, acetate, tartrate, etc. and salts useful in purifying said compounds, such as the oxalate salts and where R.sup.1 is H, the pharmaceutically acceptable carboxylate slats, such as sodium, potassium, calcium, ammonium, etc.
The intermediates of the formulae: ##SPC2## wherein R, R.sup.1, R.sup.2 and R.sup.3 are as previously described and pharmaceutically acceptable salts, thereof are also encompassed by the present invention.
In addition, this invention relates to processes for the preparation of said compounds, compositions employing said compounds and methods for utilizing said compositions as central nervous system depressants.
In addition, compounds of the formula ##SPC3##
wherein R.sup.4 is ##SPC4## ##EQU1## wherein X is hydrogen, halogen, dihalogen, CF.sub.3, NC, alkyl of 1 to 4 carbon atoms, carboethoxy, or alkoxy of 1 to 4 carbon atoms, n is zero or one, -------- represents a triple bond .tbd. when n is zero and a double bond = when n is one, and A is hydrogen or ##SPC5## R.sup.1 is as defined above; and the pharmaceutically acceptable salts thereof, are particularly preferred since they are useful as hypotensive agents as well as central nervous system depressants.
Compounds of the present invention are prepared from dialkyl [(3-hydroxy-2-pyridyl)amino]methylenemalonates via the following cyclization reaction: ##SPC6##
followed by the conversion of the above 9-hydroxy-4 -oxopyrido-[1,2-.alpha.] pyrimidine to a structure of the following type: ##SPC7##
by reacting it with a compound of the formula: EQU R.sup.5 Z
wherein R.sup.5 is R.sup.4 or a group which is readily converted into R.sup.4 ; Z represents that which is termed chemically as a leaving group, such as bromo, iodo, sulfonate, tosylate, broxylate, quaternary amine, etc.
The cyclization step is accomplished by heating in a high boiling aprotic aromatic or paraffinic solvent, such as diethylbenzene, trichlorobenzene, nitrobenzene, decahydronaphthalene, Dowtherm A (a eutectic mixture of diphenyletherdiphenyl). The reaction utilizing Dowtherm A is carried out at about 220.degree. for a period of between about 5 to about 30 minutes, preferably 15 minutes. However, it appears that during the reaction other products are formed which make purification of the product rather difficult. The compound may be purified but only after recrystallization followed by treatment with an aqueous base, such as sodium hydroxide, potassium hydroxide, etc. A second preferred procedure utilizes diethylbenzene wherein the reaction is carried out initially at about 140.degree. for approximately 1 hour then at about 180.degree. for approximately 1 hour. This preferred procedure yields a readily purifiable product. It also appears that the temperature range is rather critical since no cyclization occurs when solvents boiling considerably below 140.degree. are employed and solvents boiling appreciably above 180.degree. cause the formation of products making isolation very difficult. Thus a temperature of about 140.degree. to about 180.degree. for about 30 minutes to about 4 hours gives rise to the most convenient method for preparing the cyclized compounds of this invention.
The 9-hydroxy group is etherified by reaction with a compund of the type R.sup.5 Z, wherein R.sup.5 and Z are as previously defined and Z is preferably bromo. The reactions are generally carried out in ketonic solvents, such as acetone, methyl ethyl ketone, methyl isobutyl ketone at temperatures of from about 55.degree. to about 120.degree. for 5 to 24 hours in the presence of a base, such as potassium carbonate, potassium bicarbonate, potassium hydrogen phosphate, sodium acetate, potassium acetate, barium acetate, etc.
The essential starting materials utilized in this invention, that is the malonate esters and aminopyridines, are prepared by numerous well known procedures.
Thus the alkoxy alkylene malonate esters are prepared from ortho esters and malonate esters by standard reactions described by R. C. Fuson, W. E. Parkam and L. J. Reed [Journal of Organic Chemistry, 11, 194 (1946)] which is incorporated by reference. ##EQU2## wherein R.sup.5 may be lower alkyl, R.sup.6 may be hydrogen, lower alkyl or lower alkenyl and R.sup.7 may be lower alkyl or lower alkenyl.
The 2-amino-3-pyridinol may be substituted in either the 5- or 6-position, or both, by the substituents R.sup.2 and R.sup.3 wherein R.sup.2 and R.sup.3 are halogen, alkyl of 1 to 4 carbons or trifluoromethyl. Examples of some specific substituted 2-amino-3-pyridinols are those corresponding to the compound of formula I wherein the substituents R.sup.2 and R.sup.3 in the 5- or 6-position are as indicated in the following columns: ##SPC8## 5-position 6-position ______________________________________ F H H F F F Cl H H Cl Cl Cl Br H H Br Br Br Cl F F Cl Br F F Br Br Cl Cl Br CH.sub.3 H H CH.sub.3 CH.sub.3 CH.sub.3 F CH.sub.3 CH.sub.3 F Cl CH.sub.3 CH.sub.3 Cl Br CH.sub.3 CH.sub.3 Br F CF.sub.3 CH.sub.3 CH.sub.2 CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 Cl --CH.sub.2 CHCH.sub.3 .vertline. CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 F (CH.sub.3).sub.3 C Cl CH.sub.2 CHCH.sub.3 Br .vertline. CH.sub.3 ______________________________________
The 5-, 6-, or 5,6- R.sup.2, R.sup.3 -substituted 2-amino-3-pyridinols may be prepared according to the following reaction sequences, all temperatures being expressed in degrees Centrigrade: ##SPC9##
Compounds of this invention find utility in treating mammals, such as dogs, cats, etc. as central nervous system depressants in a dosage range of from about 4 mg. to about 50 mg. per kg, of body weight per day and generally such dosage units are employed so that a total of from about 250 mg. to about 3.5 g., preferably 750 mg. to 2.0 g. of active ingredient for a subject of about 70 kg. body weight are administered in a 24 hour period.
The preferred compounds of this invention, those of formula II, are also hypotensive agents and have a lowering effect on blood pressure. These compounds are useful in the treatment of hypertension in mammalian species, for example, rats, cats, dogs, etc., when administered in amounts ranging from about 8.0 mg. to about 100 mg. per kg. of body weight per day. A preferred dosage regimen for optimum results would be from about 12.0 mg to about 50 mg. per kg, of body weight in a single dose or divided into a series of doses.
The compounds of the present invention in the described dosages for these purposes are intended to be administered orally; however, other routes such has intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course be varied and may conveniently be beween about 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 500 mg. of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
The invention will be described in greater detail in conjunction with the following specific examples which exemplify preferred embodiments of this invention.